Sponsorship

This work has been financed by the Instituto de Salud Carlos III, Spain (http://www.isciii.es) and Fondo Europeo de Desarrollo Regional (FEDER, http://ec.europa.eu/regional_policy/es/funding/erdf/) from the European Union, through the Research Grants PI15/00794, CP09/00228, and CPII15/00032 (Per Anderson); PI12/01097, PI15/02015, and ISCIII Red de Terapia Celular (RD12/0019/0006, http://www.red-tercel.com/) (Francisco Martin); and PS09-00928 (Mario Delgado). Mario Delgado was supported by a grant (PSE-010000-2009-3) from the Ministerio de Ciencia e Innovación, Spain (http://www.idi.mineco.gob.es/), and P09-CTS-4723 from the Junta de Andalucia (Proyecto de Excelencia). Francisco Martin is funded by the Fundación Progreso y Salud (Consejería de Salud, Junta de Andalucía, http://www.juntadeandalucia.es/fundacionprogresoysalud/).

Abstract

Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising therapy for autoimmune diseases, including multiple sclerosis (MS). Administration of MSCs to MS patients has proven safe with signs of immunomodulation but their therapeutic efficacy remains low. The aim of the current study has been to further characterize the immunomodulatory mechanisms of adipose tissue-derived MSCs (ASCs) in vitro and in vivo using the EAE model of chronic brain inflammation in mice. We found that murine ASCs (mASCs) suppress T cell proliferation in vitro via inducible nitric oxide synthase (iNOS) and cyclooxygenase- (COX-) 1/2 activities. mASCs also prevented the lipopolysaccharide- (LPS-) induced maturation of dendritic cells (DCs) in vitro. The addition of the COX-1/2 inhibitor indomethacin, but not the iNOS inhibitor L-NAME, reversed the block in DC maturation implicating prostaglandin (PG) E2 in this process. In vivo, early administration of murine and human ASCs (hASCs) ameliorated myelin oligodendrocyte protein- (MOG35-55-) induced EAE in C57Bl/6 mice. Mechanistic studies showed that mASCs suppressed the function of autoantigen-specific T cells and also decreased the frequency of activated (CD11c+ and CD11c+TNF-α+) DCs in draining lymph nodes (DLNs). In summary, these data suggest that mASCs reduce EAE severity, in part, through the impairment of DC and T cell function.